Cytomegalovirus (CMV) is the leading cause of nonhereditary, congenital deafness. CMV is also recognized as the most common cause of human congenital infection, occurring in up to 2.5% of all live births. The primary pathology associated with congenital CMV is hearing loss. It is estimated that the sequelae of congenital CMV may account for as many as 40,000 nw cases of sensorineural hearing loss per year. The pathogenesis of congenital CMV infection is poorly understood at present and development of animal models has been hindered by the species-specific nature of the virus. Recently, we have been successful in establishing a guinea pig CMV (GPCMV) model of congenital CMV infection of the auditory system. This model closely resembles the auditory system physiologic and histopathologic neuropathology sen in human congenital infections. GPCMV thus provides the first experimental model system for congenital CMV induced sensorineural hearing loss. Our previous studies on newborn guinea pigs have established that primary GPCMV infection during pregnancy causes congenital GPCMV labyrinthitis and hearing loss. The neuropathology associated with congenital GPCMV infection at birth is primarily confined to the cochlea, with minimal evidence of central nervous system abnormalities. Our preliminary data indicates that, as in human infants, congenital GPCMV induced auditory system pathologies and hearing losses worsen progressively during postnatal development. Furthermore, in these animal studies the auditory pathologies appeared to spread into the central nervous system with increasing age. We now propose to utilize our established congenital infection protocol to investigate the following basic questions concerning postnatal sequelae of congenital GPCMV infection: 1) Do auditory deficits present at birth in GPCMV congenitally infected neonates remain stable or do they increase progressively during postnatal development? 2) Are asymptomatic, GPCMV congenitally infected neonates at risk for the development of auditory system pathologies and hearing loss later in life? 3) Can antiviral chemotherapy arrest or reverse the auditory system pathologies induced by congenital CMV? 4) Does postnatal immunosuppression of congenitally infected animals alter the pathogenesis of GPCMV infections in the auditory system? 5) Do middle ear infections reactivate persistent GPCMV in the auditory system of congenitally infected animals? 6) Which forms of vaccination and chemotherapy are optimal for the prevention and treatment of congenital GPCMV infection and hearing loss? An interdisciplinary approach is used to investigate the clinical symptoms, immunologic, electrophysiologic, morphologic and pathologic aspects of auditory system congenital GPCMV infections.